This invention relates to the novel process for the manufacturing of 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I, 
intermediates of formulae II and III useful in the manufacturing of such 4-oxo-1,4-dihydropyridine-2-carboxamide, and novel process for the manufacturing of the intermediates used. 
wherein:
R1, R2, R3, R6 are independently, hydrogen, lower alkyl,
R4 is lower alkyl, hydrogen, lower alkoxy,
R5 is hydrogen, an alcohol protective group, benzyl and a benzyl group optionally substituted with nitro, lower alkyl and lower alkoxy.
Lower alkyl groups include straight and branched chain hydrocarbon radicals from 1 to 6 carbon atoms.
Lower alkoxy groups include -O-[lower alkyl] wherein lower alkyl is defined above.
Alcohol protective group commonly used includes those which are well known in the art, for example, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino) carbonylbenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, 4-picolyl, heptafluoro-p-tolyl, tetrafluoro-4-pyridyl, formate, acetate, benzoate, benzyloxycarbonyl, methoxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, t-butyl.
According to further aspects of this invention, there are provided methods for the conversion compounds of formula II to 3-benzyloxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide, and 3-benzyloxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide, 3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide and 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I.
A third aspect of this invention relates to a process of reacting an acid of formula II with 1,1xe2x80x2-carbonyldiimidazole, alkylamine and an inert solvent to give a compound of formula I.
A fourth aspect of this invention concerns the process of oxidizing a compound of formula III with TEMPO, sodium hypochlorite solution, sodium bicarbonate (baking soda) and potassium bromide to give a compound of formula II.
This invention relates to certain 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I as orally active iron chelators. Members of the 3-hydroxy-4-oxo-1,4-dihydropyridine class are well known for their ability to chelate iron in physiological environment and these have been reported as useful in the treating iron related disorders such as thalassaemia and anemia, see U.S. Pat. No. 4,840,958, U.S. Pat. No. 5,480,894, U.S. Pat. No. 5,688,815, J. Med. Chem. 1999, 42(23), 4818-4823.
3-Hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide are bidentate iron I chelators with potential for oral administration, see Bioorganic and Medicinal Chemistry 9 (2001), 563-567. A patent application has been published emphasizing the pharmacological properties of this class of compound, see WO98/54318. Compounds of formula I have been tested in iron mobilization efficacy assay in rat via the mode of oral administration. The results are reported in Table 3 of WO98/54318. Compounds of formula I are chelators possessing high pFe3+ values and show great promise in their ability to remove iron under in-vivo conditions.
3-Hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide has been prepared by the method, described in examples 45 to 48, 53, and 58 of WO98/54318. Allomaltol (1) is converted to 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) according to the procedure described in FR1516463. The 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) is reacted with benzyl bromide in sodium hydroxide in a 10:1 mixture of methanol and water to give the 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3) which is then oxidized with diemthyl sulfoxide and sulfur trioxide.pyridine complex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (4). Oxidation of the 2-formyl derivative with sulfamic acid and sodium hypochlorite in acetone and water affords 2-carboxyl-3-benzyloxy-6-methyl-pyran4(1H)-one (5). The 2-carboxyl derivative is reacted with dicyclohexyldiimide and 2-mercaptothiazoline and 4-dimethylaminopyridine to give the 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (6) which is reacted with methylamine in tetrahydrofuran to give 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7). The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7) is converted to 1,6-dimethyl-3-benzyloxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (8) with methylamine in alcohol. The 3-benzyloxy derivative was deprotected with hydrogenation using Pd/C in dimethylformamide as illustrated in Scheme 1 to give 1,6-dimethyl-3-hydroxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (9): 
Scheme 1: a. HCHO, NaOH; b. PhCH2Br, NaOH, MeOH, H2O; c. DMSO, SO3.pyridine, CHCl3, Et3N; d. sulfamic acid, NaClO2, acetone, water; e. DCC, CH2Cl2, 2-mercaptothiazoline; f. MeNH2, THF; g. MeNH2, MeOH; h. H2, Pd/C, EtOH.
The IUPAC name of the chemicals shown in Scheme 1 is further clarified below:
Compound (3): 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran4(1H)-one has an alternate IUPAC name 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one.
Compound (5): 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one has an alternate IUPAC name 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid.
Compound (8): 1,6-dimethyl-3-benzyloxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide has an alternate IUPAC name: 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.
Compound (9): 1,6-dimethyl-3-hydroxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide has an alternate IUPAC Name: 3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.
When compared to the above process, the applicant""s invention introduces a number of advantages over the existing process:
1. It affords 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide in considerably higher yields than existing procedures.
2. It is amenable to industrial scale production since 3-hydroxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide can be made in less process steps from economically, commercially available reagents.
3. It avoids the use of oxidizing agent such as DMSO, sulfur trioxide.pyridine and the need for column chromatography using diethyl ether and the isolation of the intermediate 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one. It avoids the generation of large amount of industrial waste and the execution of the synthesis in two distinct separate steps for the conversion of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to 3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one. The conversion of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to 3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one is achieved in one single process step using baking soda (sodium bicarbonate), sodium hypochlorite solution, and TEMPO. The labour cost is significantly reduced because of the short reaction time and ease of work-up.
4. It avoids the isolation and purification of intermediates such as 3-hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1H)-one, 3-benzyloxy-2-formyl-6-methyl-pyran-4(1H)-one, 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide. The isolation of these intermediates involve extra process step, labour cost, and waste disposal, thereby rendering the process more expensive.
5. It eliminates the use of intermediate 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione. It does not use 2-mercaptothiazoline which requires its removal as chemical waste in the later step.
6. It avoids the use of reagent dicyclohexyldiimide and the generation of dicyclohexylurea waste that are skin irritant.
7. It does not require three distinct steps for the conversion of 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to 3-benzyloxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide. The conversion is achieved in one single process step. The labour cost is significantly reduced because of the short reaction time and ease of work-up.
8. An efficient process is described for the large scale manufacturing of 2-chlorokojic acid, a key intermediate for the synthesis of allomaltol. The existing literature process is not amenable to large scale synthesis.
Therefore, one object of the invention is to provide novel process for the production of 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide and 1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide from readily available, inexpensive and relatively safe starting material. Other objects of this invention can be recognized by those skills in the art from the summary of invention and detailed description of embodiments thereof.

According to one aspect of the invention, a process is provided to make the compound of formula I which comprises of the step of oxidation of III to the acid of formula II in a single process step as shown in scheme 2. The oxidants are TEMPO, baking soda, sodium hypochlorite and potassium bromide. Compound II is then reacted with 1,1xe2x80x2-carbonyldiimidazole and methylamine in an inert solvent to give a compound of formula I in a single process step. The alcohol protective group R5 can be deprotected to give a compound of formula I wherein R5 is hydrogen. The compound of formula III is in turn prepared from the compound of formula IV in a single process step.
Allomaltol (compound of formula IV wherein R1=Me, R4=H, R5=H) is reacted with formaldehyde in a sodium hydroxide solution in methanol and water for a period of 6 to 16 hrs. Benzyl chloride was added and the reaction was heated to reflux for 4 to 12 hours, preferably 6 hours. The benzylated alcohol (compound of formula III wherein R1=Me, R4=H, R5=CH2Ph) is isolated by traditional means. This procedure eliminates the use of a more expensive reagent benzyl bromide and the need to isolate the diol intermediate 3-hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1H)-one. The preparation is achieved in one manufacturing process step. The amount of methanol is critical for the success of the experiment, the preferred amount of solvent mixture is methanol and water in the ratio of 3:2.
The alcohol III is then oxidized to the acid (compound of formula If wherein R1=Me, R4=H, R5=CH2Ph) in a single process step. Jones reagent (chromium trioxide in sulfuric acid) converts the compound III to acid II in acetone, but the yield is extremely low and is less than 10%. A large amount of chromium waste is created. However, TEMPO, sodium hypochlorite, baking soda and potassium bromide affords the acid in very good yield, without chromatography and further recrystallization. The reaction is carried out in an ice bath, with the internal reaction temperature of less than 10xc2x0 C. The reagents are extremely cheap and the reaction time is less than 24 hours. TEMPO is used in catalytic amount.
The acid II is converted to the amide I in one single process step. The acid is reacted with 1,1xe2x80x2-carbonyldiimidazole in an inert solvent over a period of several hours. A solution of methylamine in alcohol is added. Elevation of the reaction temperature to between 60 to 100xc2x0 C., preferably 70 to 80xc2x0 C. for a few hours, affords the amide (compound of formula I wherein R1=Me, R2=Me, R3=Me, R6=H, R4=H, R5=CH2Ph) in a single manufacturing step. The 3-benzyl alcohol protective group (compound of formula I wherein R5=CH2Ph) can be removed by hydrogenation reaction or by acid. Procedures for the removal of protective group can be found in Greene, T. W., in Protective Groups in Organic Synthesis, John Wiley and Sons, 1981.
The starting materials required in this process are commercially available in kilogram to metric ton quantities. Allomaltol is prepared from the zinc reduction of 2-chlorokojic acid. The literature reported the use of excess thionyl chloride for the preparation of 2-chlorokojic acid. The reaction is heterogeneous and the procedure is not amenable to large scale synthesis and manufacture. However, 2-chlorokojic acid can be prepared from kojic acid using 1 to 1.2 equivalent thionyl chloride in an inert solvent. The preferred inert solvent is acetonitrile and the product is easily isolated by filtration.
The above description details a general method for the conversion of compound III to II then to compound I.
The present invention will be more fully understood by the following examples which illustrate the invention, but are not considered limiting to the scope of the invention.